Control of gene expression underlies, at some level, all cellular and/or organismal processes, including direction of the development of the organism and cellular responses to outside signals. Gene control occurs at several points in the cellular response, including the activation or suppression of transcription, the differential processing and stabilization of messenger RNA (mRNA), and the extent of translation of the mRNA. Control of transcription plays a particularly critical role in the regulation of gene expression in eukaryotic cells. (See generally, Darnell et al., 1990, Molecular Cell Biology, 2d ed., Chapter 11, W.H. Freeman & Co., NY, pp. 391-448).
Cellular mechanisms mediate the activation of transcription of specific genes, for example, the activation of transcription elicited during development and that elicited by extracellular signals such as hormones or growth factors. In particular, transcription of a specific mRNA coding for a particular gene product is controlled by a set of transcription factor proteins. These proteins bind specific DNA sequences, either promoter or enhancer elements, and form multimeric complexes which activate transcription (Tjian and Maniatis, 1994, Cell 77:5-8). The multitude and cell specificity of the transcription factors and corresponding DNA binding sites allow for the precise regulation of transcription. Thus, the regulation of transcription activation would provide a precise and specific method for controlling the production of particular proteins.
Previous work has suggested that the presence of the 3' untranslated region (UTR) of a certain mRNA may affect the transcription of a select gene or group of genes. Rastinejad and Blau (1993, Cell 72:903-917) showed that the 3' UTRs of the muscle structural genes, troponin, tropomyosin, and .alpha.-cardiac actin-enhanced muscle-specific gene expression. The authors suggest, among a variety of potential mechanisms, that the RNA sequences play a role in the transcriptional activation of these genes.
Other work has suggested that the clustering of promoter sequences within and around genes may assist in the recruitment of required transcription factors to the vicinity of active promoter elements in the interphase nucleus (Bodnar and Ward, 1987, Nucleic Acids Research 15:1835-51). Thus, it appears that these sequences may act to specifically concentrate these factors so that the factors are available to activate transcription quickly at the appropriate point in the cell cycle.
While activation of transcription has been studied intensely, gene control through the suppression or inhibition of transcription has not. Thus, although most genes are repressed in most all types, little is known about the mechanisms that comprise selective gene repression during embryogenesis, organogenesis and differentiation (Herschbach and Johnson, 1993, Ann. Rev. Cell Biol. 9:479-509).